Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, Perth, Western Australia, Australia.
PLoS One. 2012;7(12):e52812. doi: 10.1371/journal.pone.0052812. Epub 2012 Dec 26.
Naltrexone is not recommended during pregnancy. However, sustained-release naltrexone implant use in humans has resulted in cases of inadvertent foetal exposure. Here, we used clinically relevant dosing to examine the effects of maternally administered sustained-release naltrexone on the rat brain by examining offspring at birth and in adulthood. Maternal treatment (naltrexone or placebo implant) started before conception and ceased during gestation, birth or weaning. Morphometry was assessed in offspring at birth and adulthood. Adult offspring were evaluated for differences in locomotor behaviour (basal and morphine-induced, 10 mg/kg, s.c.) and opioid neurochemistry, propensity to self-administer morphine and cue-induced drug-seeking after abstinence. Blood analysis confirmed offspring exposure to naltrexone during gestation, birth and weaning. Naltrexone exposure increased litter size and reduced offspring birth-weight but did not alter brain morphometry. Compared to placebo, basal motor activity of naltrexone-exposed adult offspring was lower, yet they showed enhanced development of psychomotor sensitization to morphine. Developmental naltrexone exposure was associated with resistance to morphine-induced down-regulation of striatal preproenkephalin mRNA expression in adulthood. Adult offspring also exhibited greater operant responding for morphine and, in addition, cue-induced drug-seeking was enhanced. Collectively, these data show pronounced effects of developmental naltrexone exposure, some of which persist into adulthood, highlighting the need for follow up of humans that were exposed to naltrexone in utero.
纳曲酮在怀孕期间不建议使用。然而，在人类中使用缓释纳曲酮植入物已导致胎儿意外暴露的情况。在这里，我们使用临床相关剂量，通过检查出生和成年后代来研究母体给予缓释纳曲酮对大鼠大脑的影响。母体治疗（纳曲酮或安慰剂植入物）在受孕前开始，并在妊娠、分娩或断奶期间停止。在出生和成年时评估后代的形态测量。评估成年后代的运动行为（基础和吗啡诱导，10mg/kg，皮下）和阿片类神经化学差异、自行给予吗啡的倾向以及禁欲后线索诱导的觅药行为。血液分析证实了胎儿在妊娠、分娩和断奶期间接触纳曲酮。纳曲酮暴露增加了产仔数并降低了后代的出生体重，但不改变大脑形态测量。与安慰剂相比，纳曲酮暴露的成年后代的基础运动活动较低，但对吗啡的精神运动敏化发展增强。发育性纳曲酮暴露与成年期纹状体前强啡肽原 mRNA 表达对吗啡诱导的下调抵抗有关。成年后代还表现出对吗啡的更大操作性反应，此外，线索诱导的觅药行为增强。总之，这些数据表明，发育性纳曲酮暴露会产生明显的影响，其中一些影响持续到成年期，这突出表明需要对在子宫内暴露于纳曲酮的人类进行随访。
